The unifying goal of this project is the elucidation of intra-ovarian mechanisms that regulate a) follicle growth and atresia, and b) the size of the species-characteristic ovulatory quota during the mammalian ovarian cycle. The studies proposed are designed to test the hypothesis that the ovarian (follicular) microvasculature is not merely a passive conduit, but is, instead, an important locus of intra-ovarian regulation of follicle growth, i.e. providing certain follicles differential, access to gonadotropins and other extraovarian factors. Differential access to extraovarian factors may account for why some follicles of a cohort continue to mature while others succumb to atresia. A resting, primordial follicle lacks a discrete (individual) vascular supply, but as it grows a follicle "captures" a discrete blood supply, as a capillary wreath, in the theca layer which develops around it. I hypothesize that healthy, growing follicles secrete a specific angiogenic substance that a) attracts capillary endothelial cells (chemotaxis), and b) stimulates growth of the investing capillary wreath to "match" it to follicle growth (mitogenesis). The angiogenic capability of a follicle may provide a biochemical and cellular mechanism for differential access by affecting blood flow and the total surface area for transcapillary efflux by diffusion. An in vitro approach is proposed to make this complex problem more tractable experimentally. Organotypic culture of isolated whole follicles will be employed to determine if healthy follicles secrete a specific angiogenic substance that will be mitogenic and chemotactic to cultured vascular endothelial cells. Cell culture of isolated follicular components, granulosa and theca cells, will be used to identify the cellular origin of the putative angiogenic factor. Direct effects of gonadotropins and ovarian steroids and other factors on growth and pinocytotic activity (permeability) of cultured capillary endothelial cells will also be examined. If successful, this project will have demonstrated a novel physiological mechanism regulating folliculogenesis. A better understanding of the regulation of folliculogenesis will contribute to the scientific basis for rational therapy of infertility problems and for programs of population control.